Lymphocyte activation is required for HIV-1 replication. Antigen stimulation of CD4+ T cells leads to enhanced viral replication both in vitro and in vivo. The pulmonary compartment represents an important site of antigen exposure, and pulmonary infections have been shown to result in increase in both local and systemic viral replication, as well as pulmonary and systemic immune deterioration. We have developed a novel in vitro model for studying HIV-1 replication during antigen presenting cell in the context of antigen presentation. We have shown that during the response to antigen, both antigen-specific and non-antigen specific (bystander) cells are activated. In preliminary studies, we observed that antigen-specific and bystander cells differ in their susceptibility to HIV-1 infection, that viral replication is occurring predominantly in the bystander-activated cells, and that viral strains may differ in their tropism for antigen-specific versus bystander cells. This has important implications in understanding the mechanisms of viral regulation and immune cell depletion in the pulmonary compartment. Our hypothesis is that immune stimulation and consequent cell-cell interactions within the pulmonary compartment result in local immune activation, HIV-1 replication in specific cellular subsets, and immune cell depletion and dysfunction. These interactions play a central role in pulmonary HIV pathogenesis. To better the mechanisms responsible for antigenic stimulation and viral replication during immune cell interactions in the lung, we will: (1) identify and characterize the sub-populations of activated CD4+ T cells produced during an APC-driven immune response to pulmonary pathogens such as S. pneumonia, M. tuberculosis and influenza virus; (2) define the populations of activated CD4+ T cells responsible for HIV-1 replication in the pulmonary compartment, and; (3) identify the mechanisms responsible for resistance or permissiveness to infection in the sub-populations of activated cells. We anticipate that these studies will lead to greater understanding of the mechanisms underlying immune cell depletion in the lung in AIDS and, ultimately, provide a rational basis for the development of therapeutic strategies designed to modulate these interactions. The development of such immune-based therapies might lead to improved vaccine efficacy by increasing antigen-specific activation without enhanced viral replication and its deleterious consequences on lung and systemic immune function.